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- PDB-4nqm: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 4nqm
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a triazolo-phthalazine ligand
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/INHIBITOR / STRUCTURAL GENOMICS CONSORTIUM / SGC / BROMODOMAIN / INHIBITION / Transcription / Small molecule inhibitor / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II ...RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / p53 binding / chromosome / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
SUCCINIC ACID / Chem-Y1Z / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.58 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Felletar, I. / Martin, S. / Fedorov, O. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: To be Published
Title: Crystal Structure of the first bromodomain of human BRD4 in complex with a triazolo-phthalazine ligand
Authors: Filippakopoulos, P. / Picaud, S. / Felletar, I. / Martin, S. / Fedorov, O. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S.
History
DepositionNov 25, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7523
Polymers15,0991
Non-polymers6532
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.510, 46.570, 62.380
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 1 / Fragment: UNP residues 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical ChemComp-Y1Z / 2-chloro-N-[5-(3-methyl[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-2-(morpholin-4-yl)phenyl]benzenesulfonamide


Mass: 535.017 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H23ClN6O3S
#3: Chemical ChemComp-SIN / SUCCINIC ACID


Mass: 118.088 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 166 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.19 Å3/Da / Density % sol: 43.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M SPG pH 8.0, 60.0% MPD, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Oct 21, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionRedundancy: 3.9 % / Av σ(I) over netI: 10.9 / Number: 72719 / Rsym value: 0.049 / D res high: 1.575 Å / D res low: 28.857 Å / Num. obs: 18694 / % possible obs: 98.7
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
4.9828.8699.510.0260.0263.7
3.524.9810010.0220.0224
2.883.5210010.0320.0324.1
2.492.8810010.0410.0414.1
2.232.4910010.0590.0594.1
2.032.2399.910.0740.0744.1
1.882.0399.610.1160.1164.1
1.761.8899.210.1970.1974.1
1.661.7698.710.320.324
1.581.6693.510.4390.4392.8
ReflectionResolution: 1.58→28.86 Å / Num. all: 18940 / Num. obs: 18694 / % possible obs: 98.7 % / Redundancy: 3.9 % / Biso Wilson estimate: 19.7 Å2 / Rmerge(I) obs: 0.049 / Rsym value: 0.049 / Net I/σ(I): 15.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.58-1.662.80.439222120.43998.7
1.66-1.7640.323.824720.3299.6
1.76-1.884.10.1976.323210.19799.7
1.88-2.034.10.11610.522000.11699.9
2.03-2.234.10.07416.120300.07499.9
2.23-2.494.10.05919.518620.059100
2.49-2.884.10.04124.916720.04199.9
2.88-3.524.10.03233.914440.03299.9
3.52-4.9840.02245.111360.02299.8
4.98-28.863.70.02636.46810.02699.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å28.86 Å
Translation2.5 Å28.86 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASER2.3.0phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.58→28.86 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.955 / WRfactor Rfree: 0.1863 / WRfactor Rwork: 0.1507 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8991 / SU B: 2.667 / SU ML: 0.051 / SU R Cruickshank DPI: 0.0869 / SU Rfree: 0.0882 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.087 / ESU R Free: 0.088 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2025 958 5.1 %RANDOM
Rwork0.1678 17692 --
obs0.1696 18650 98.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 77.87 Å2 / Biso mean: 18.8339 Å2 / Biso min: 7.09 Å2
Baniso -1Baniso -2Baniso -3
1-0.61 Å20 Å20 Å2
2---0.32 Å20 Å2
3----0.28 Å2
Refinement stepCycle: LAST / Resolution: 1.58→28.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1056 0 45 166 1267
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.021166
X-RAY DIFFRACTIONr_bond_other_d0.0020.02797
X-RAY DIFFRACTIONr_angle_refined_deg1.6662.0171598
X-RAY DIFFRACTIONr_angle_other_deg0.9831967
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2655135
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.83225.92654
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.07515205
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.399153
X-RAY DIFFRACTIONr_chiral_restr0.0920.2166
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211258
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02217
LS refinement shellResolution: 1.58→1.616 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.481 63 -
Rwork0.563 1084 -
all-1147 -
obs--88.3 %
Refinement TLS params.Method: refined / Origin x: 15.7749 Å / Origin y: -6.6042 Å / Origin z: -4.8099 Å
111213212223313233
T0.0383 Å2-0.0011 Å20.007 Å2-0.0476 Å20.0043 Å2--0.0494 Å2
L0.1884 °2-0.1561 °20.0409 °2-0.2718 °2-0.1396 °2--0.6132 °2
S-0.001 Å °-0.0217 Å °-0.0209 Å °-0.012 Å °0.0187 Å °0.0117 Å °0.0204 Å °-0.0182 Å °-0.0176 Å °

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